Borano-nucleotides: new analogues to circumvent HIV-1 RT-mediated nucleoside drug-resistance

Karine Alvarez (1) , Jérôme Deval (1) , Boulbaba Selmi (1) , Karine Barral (1) , Joelle Boretto (1) , Catherine Guerreiro (2) , Laurence S Mulard (2) , Robert Sarfati (2) , Bruno Canard (1)

1 AFMB - Architecture et fonction des Macromolécules Biologiques - UMR 6098
2 Chimie des Biomolécules - Chemistry of Biomolecules

Alpha-boranophosphates suppress RT-mediated resistance when the catalytic rate of incorporation (kpol) of the analogue 5'-triphosphate is responsable for drug resistance, such as in the case of K65R mutant and ddNTPs, and Q151M toward AZTTP and ddNTPs. This suppression is also observed with BH3-d4T and BH3-3TC toward their clinically relevant mutants Q151M and M184V. Moreover, the presence of the borano (BH3-) group renders the incorporation of the analogue independent from amino-acid substitutions in RT. To our knowledge, this is the first example of rescue of polymerase activity by means of a nucleotide analogue

Domains: Chemical Sciences; Chemical Sciences; Medicinal Chemistry

Karine Alvarez, Jérôme Deval, Boulbaba Selmi, Karine Barral, Joelle Boretto, et al.. Borano-nucleotides: new analogues to circumvent HIV-1 RT-mediated nucleoside drug-resistance. Nucleosides, Nucleotides and Nucleic Acids, 2005, 24 (5-7), pp.419-422. ⟨10.1081/NCN-200059951⟩. ⟨hal-02061659⟩